Progress to Date
After years of research demonstrating the extent of this problem, coupled with advocacy by national professional societies in paediatrics and child health, there was movement in this area when the Pediatric Pharmacology Research Unit (PPRU) network was established in the United States by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 1994. This network – a group of first seven and then thirteen academic health care centre which operated from 1994 to 2010 – had the mandate to improve the paediatric labelling of both new drugs and drugs already on the market by conducting collaborative research with academia, industry and health care providers (42). Over the life span of the PPRU, a number of advances were made in understanding the impact of ontogeny on therapy for children and in the design and conduct of drug studies in infants and children.
The development of the PPRU network was accompanied by legislative change, the first being the Pediatric Labelling Rule of 1994, issued by the US FDA. This rule, which requested industry to submit paediatric data, was fairly ineffective in enhancing paediatric labelling and thus in 1997 the FDA Modernization Act (FDAMA) was passed (43). FDAMA provided incentives for companies to include paediatric data in new drug submissions by extending 6 months of patent protection for drugs when submission includes paediatric data. Failing to achieve the desired effect, in 1998, the first iteration of a “Pediatric Rule” was enacted which mandated paediatric studies for not only new drugs but also for any label changes on already approved and marketed drugs. This rule, however, was challenged in Federal court and was ultimately struck down in 2002, citing Agency overreach.
Despite this early setback, the United State Congress persisted, and the Best Pharmaceuticals for Children Act (BPCA) passed in 2002 while the Pediatric Research Equity Act (PREA) passed a year later in 2003. Together, these two pieces of legislation imposed a regulatory requirement for pharmaceutical companies to evaluate drugs in paediatric populations if they were likely to be used in children, irrespective of the indication for which approval was sought (43).
The provision of paediatric exclusivity was successful in having paediatric-specific data on the project monograph when an FDA request for paediatric data was issued in 92% of all requests for which exclusivity was granted from 1998 to 2012 (44). This provision allows six additional months of patent exclusivity to manufacturers who conduct paediatric drug studies and have a Pediatric Study Plan (PSP). However, of 401 requests made by the FDA exclusivity was only granted in 189 cases, i.e. the majority of requests did not result in new paediatric data or indications (44). This was influenced by both therapeutic area and year of exclusivity, with requests made in the areas of gastroenterology and pain and requests made in the early years of the program being more likely to result in additional paediatric data or indications (44).
Similar regulatory progress has been made internationally. In Europe, the European Medicines Agency (EMA), after studying developments in the United States, enacted the Paediatric Regulation in 2007 with the goal of enhancing the development, availability and safety of medications for children in the European Union (45). An important aspect of the Regulation was the requirement for a Paediatric Investigation Plan (PIP) for all new drug submissions except when a waiver or deferral is granted, as in the case of a drug that will not in any reasonable likelihood used for children. The Regulation also established a Paediatric Committee to determine which studies must be carried out as part of the PIP. The FDA requires a Pediatric Study Plan and also has a Pediatric Expert Committee.
A ten year analysis of the implementation of the Paediatric Regulation demonstrated that there had been a substantial increase in the number of medications with paediatric data and/or indications, notably in the areas of rheumatology and anti-infective agents. However, in diseases largely confined to children alone or where there were substantial differences in disease course between adults and children there was much less progress. As a consequence, the EMA and the Paediatric Committee created an action plan to enhance implementation of the Regulation. The action plan includes identifying paediatric medical needs, strengthening cooperation between decision makers, ensuring the timely completion of PIPs, improving how PIPs are handled and increasing transparency around paediatric medicines.
While both the US FDA and the European Union’s EMA had common goals to enhance the development of more safe and effective therapeutics for children they have pursued slightly different approaches (Table 1) (45). As an example, the FDA had two separate sets of legislation – BCPA and PREA – to drive drug development for children with a third - Research to Accelerate Cures and Equity for Children Act (the RACE Act) being introduced in 2017 while the EU has a single piece of legislation, reducing the number of requirements and legal frameworks to be negotiated. This does not, however, necessarily mean that it is easier to navigate the EMA’s paediatric requirements as opposed to the FDA. While there are other differences overall this legislative approach in both the US and the European Union not only is the goal the same but so are the scientific elements driving paediatric investigation, including but not restricted to descriptions of products and diseases, development plans for age-appropriate formulations and timing of studies (45).
The developments in the US and European Union to move paediatric drug development forward have stimulated changes in the approach to paediatric drug approval and regulation in a number of countries although the US and the European Union remain the only two large jurisdictions to have comprehensive paediatric drug development strategies supported by legislation although some smaller jurisdictions such as Switzerland that require paediatric data, often via the approval of an approved PIP or PSP (26, 46-48).